Glioblastoma is resistant to conventional treatments and has dismal prognosis. Despite promising in vitro data, molecular targeted agents have failed to improve outcomes in patients, indicating that conventional two-dimensional (2D) in vitro models of GBM do not recapitulate the clinical scenario. Responses of primary glioblastoma stem-like cells (GSC) to radiation in combination with EGFR, VEGF, and Akt inhibition were investigated in conventional 2D cultures and a three-dimensional (3D) in vitro model of GBM that recapitulates key GBM clinical features. VEGF deprivation had no effect on radiation responses of 2D GSCs, but enhanced radiosensitivity of GSC cultures in 3D. The opposite effects were observed for EGFR inhibition. Detailed analysis of VEGF and EGF signaling demonstrated a radioprotective role of Akt that correlates with VEGF in 3D and with EGFR in 2D. In all cases, positive correlations were observed between increased radiosensitivity, markers of unrepaired DNA damage and persistent phospho-DNA-PK nuclear foci. Conversely, increased numbers of Rad51 foci were observed in radioresistant populations, indicating a novel role for VEGF/Akt signaling in influencing radiosensitivity by regulating the balance between nonhomologous end-joining and homologous recombination-mediated DNA repair. Differential activation of tyrosine kinase receptors in 2D and 3D models of GBM explains the well documented discrepancy between preclinical and clinical effects of EGFR inhibitors. Data obtained from our 3D model identify novel determinants and mechanisms of DNA repair and radiosensitivity in GBM, and confirm Akt as a promising therapeutic target in this cancer of unmet need.

Frequency of vascular abnormalities in spontaneous SAH is lower than the traditionally quoted figure, which has diagnostic and prognostic implications for patient management.

We investigated uptake of short-course chemo-radiotherapy and compared outcomes with other treatment schedules in elderly patients with glioblastoma (GBM). Methods: Patients aged 65 or over with a diagnosis of GBM were identified from an 18-month period from three centers in the UK. The primary end point of this study was overall survival from the date of diagnosis. Results: The analysis included 210 patients. Overall median survival was 5.0 months. Approximately 31.9% of patients received combined chemoradiation; multivariate analysis showed that patients who received standard chemoradiation were at a reduced risk of death than those receiving hypofractionated chemoradiation. Discussion: In this retrospective study, patients treated with standard chemoradiation experienced better outcomes than patients receiving hypofractionated chemoradiation. Patient selection likely contributed to these findings.

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